Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention is directed to solid dosage formulations containing a combination of valsartan, amlodipine and a diuretic such as hydrochlorothiazide, as well as to methods of making such solid dosage forms and a method of treating a subject with such solid dosage forms.
• fixed-combination refers to a combination of two or more drugs or active ingredients presented in a single dosage unit such as a tablet or a capsule; further as used herein, “free-combination” refers to a combination of two or more drugs or active ingredients dosed simultaneously but as two or more dosage units.
• free-combination refers to a combination of two or more drugs or active ingredients dosed simultaneously but as two or more dosage units.
• the objective is to provide a patient-convenient combination dosage form of active ingredients that is bioequivalent to the corresponding free-combination of the same active ingredients and/or delivers a superior pharmacodynakic effect than the individual components.
• Development of fixed-combination dosage formulations that are bioequivalent to the free-combination is challenging due to the multiplicity of challenges arising from pharmacokinetic and pharmaceutical properties of the drugs sought to be combined.
• valsartan has an absolute oral bioavailability of only about 25% with a wide range of 10-35%.
• Valsartan also has pH dependent solubility whereby it ranges from very slightly soluble in an acidic environment to soluble in a neutral environment of the gastrointestinal tract.
• Amlodipine besylate is slightly soluble in water and has an absolute bioavailability of 64-90%.
• Hydrochlorothiazide is slightly soluble in water and has an oral bioavailability 60-80%.
• the present invention is directed to a solid dosage form comprising a combination of valsartan, amlodipine and hydrochlorothiazide, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms.
• amlodipine free base is provided in the form of amlodipine besylate, and the pharmaceutically acceptable additives are selected from diluents, disintegrants, glidants, lubricants, binders, colorants and combinations thereof.
• the solid dosage form is a monolayer tablet.
• the solid dosage form is a bilayer tablet, e.g., having the valsartan and the hydrochlorothiazide in one layer and the amlodipine in another layer or having the valsartan in one layer and the amlodipine and the hydrochlorothiazide in another layer or having the valsartan and the amlodipine in one layer and the hydrochlorothiazide in another layer.
• the solid dosage form is a trilayer tablet, e.g., having all three actives in separate layers.
• the amount of valsartan employed in such solid dosage forms, monolayer or bilayer preferably ranges from about 40 mg to about 640 mg, preferably 80 mg to 640 mg, and more preferably is 160 mg or 320 mg.
• the amount of amlodipine employed in such solid dosage forms, monolayer or bilayer preferably ranges from about 2.5 mg to about 20 mg, and more preferably is 5 mg or 10 mg.
• the amount of hydrochlorothiazide employed in such solid dosage forms, monolayer or bilayer preferably ranges from about 6.25 mg to about 50 mg, and more preferably is 12.5 mg or 25 mg.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) blending valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the second embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine and hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the fourth embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, amlodipine, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the sixth embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, hydrochlorothiazide, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZmade according to the method of the eighth embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation; (b) granulating amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine granulation; and (c) compressing the valsartan granulation and the amlodipine granulation together to form a bilayer solid dosage form, wherein hydrochlorothiazide is present in the valsartan granulation and/or the amlodipine blend.
• step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.
• step (b) comprises a granulation process with the steps of (bl) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form an amlodipine granulation.
• Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form.
• Hydrochlorothiazide can be incorporated at step al and/or a6, and at step bl and/or b6.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the tenth embodiment.
• this invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a valsartan granulation; (b) granulating hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a hydrochlorothiazide granulation; and (c) compressing the valsartan granulation and the hydrochlorothiazide granulation together to form a bilayer solid dosage form, wherein amlodipine is present in the valsartan granulation and/or the hydrochlorothiazide blend.
• step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.
• step (b) comprises a granulation process with the steps of (bl) blending hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form a hydrochlorothiazide granulation.
• Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form.
• Amlodipine can be incorporated at step al and/or a6, and at step bl and/or b6.
• Yet another embodiment of the invention is directed to a method of treating hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure comprising administering a solid dosage form of valsartan, amlodipine and hydrochlorothiazide to a subject in need of such treatment.
• the solid dosage form is orally administered to the subject.
• the present invention relates to solid dosage forms which contain a combination of valsartan, amlodipine and hydrochlorothiazide.
• the first embodiment of the invention is directed to a solid dosage form comprising a combination of valsartan, amlodipine and hydrochlorothiazide, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms.
• the solid dosage forms of the present invention can take the form of monolayer tablets (having the valsartan, the amlodipine and the hydrochlorothiazide in one layer) or bilayer tablets (e.g., having the valsartan in one layer and the amlodipine and the hydrochlorothiazide in another layer or having the valsartan and the hydrochlorothiazide in one layer and the amlodipine in another layer or having the valsartan and the amlodipine in one layer and the hydrochlorothiazide in another layer) or trilayer tablets (e.g., having the valsartan, amlodipine and hydrochlorothiazide all in separate layers.) or a trilayer tablet of two active layers ( amlodipine+HCTZ, amlodipine + valsartan) separated by a non-active layer and a third layer of valsartan or HCTZ or amlodipine.
• Valsartan ((S)-N-valeryl-N- ⁇ [2'-(lH-tetrazole-5-yl)-biphenyl-4-yl]-methyl ⁇ - valine) suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. For example, the preparation of valsartan is described in U.S. Patent No. 5,399,578, the entire disclosure of which is incorporated by reference herein. Valsartan may be used for purposes of this invention in its free form as well as in any suitable salt form.
• Valsartan is employed in an amount typically ranging from about 40 mg to about 640 mg, preferably from about 80 mg to about 320 mg, and more preferably is about 160 mg or about 320 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet.
• the amount of valsartan noted above refers to the amount of free valsartan or salt thereof present in a given solid dosage form.
• Amlodipine (3-ethyl-5-methyl-2(2-aminoethoxymethyl)-4-(2-chlrorophenyl)- l,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate) suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. Amlodipine may be used for purposes of this invention in its free form as well as in any suitable salt form; in a preferred embodiment of this invention, amlodipine free base is supplied to the solid dosage forms through the use of amlodipine besylate.
• Amlodipine is employed in an amount ranging from 2.5 mg to about 20 mg, preferably from about 5 mg to about 10 mg, and more preferably is about 5 mg or about 10 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet.
• the amount of amlodipine noted above refers to the amount of free amlodipine present in a given solid dosage form.
• Hydrochlorothiazide suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods.
• Hydrochlorothiazide may be used for purposes of this invention in its free form as well as in any suitable salt form.
• Hydrochlorothiazide is employed in an amount ranging from 6.25 mg to about 50 mg, preferably from about 12.5 mg to about 25 mg, and more preferably is about 12.5 mg or about 25 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet.
• the amount of hydrochlorothiazide noted above refers to the amount of free hydrochlorothiazide present in a given solid dosage form.
• additives suitable for use in the present invention include, without limitation, diluents or fillers, disintegrants, glidants, lubricants, binders, colorants and combinations thereof.
• the amount of each additive in a solid dosage formulation may vary within ranges conventional in the art.
• Suitable diluents include, without limitation, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, sucrose or other sugars or sugar derivatives, low- substituted hydroxypropyl cellulose, di-calcium phosphate, lactose, and combinations thereof.
• a diluent may be employed in an amount ranging from about 10% to about 80%, preferably from about 32% to about 51% by weight of the solid dosage form (prior to any optional film coating).
• a diluent is preferably employed in an amount ranging from about 10% to about 80%, more preferably in an amount ranging from about 32% to about 39% by weight of the solid dosage form.
• a diluent is preferably employed in an amount ranging from about 10% to about 80%, more preferably in an amount ranging from about 47% to about 51% by weight of the solid dosage form.
• Suitable disintegrants include, without limitation, crospovidone, sodium starch glycolate, L-hydroxy propyl cellulose, croscarmellose sodium, and combinations thereof.
• a disintegrant may be employed in an amount ranging from about 0.5% to about 50%, preferably from about 5% to about 14% by weight of the solid dosage form (prior to any optional film coating).
• a disintegrant is preferably employed in an amount ranging from about 0.5% to about 50%, more preferably in an amount ranging from about 5% to about 14% by weight of the solid dosage form.
• a disintegrant is preferably employed in an amount ranging from about 0.5% to about 50%, more preferably in an amount ranging from about 7% to about 10% by weight of the solid dosage form.
• Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof.
• a glidant may be employed in an amount ranging from about 0.1% to about 10%, preferably from about 0.6% to about 0.8% by weight of the solid dosage form (prior to any optional film coating).
• a glidant is preferably employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 0.75% by weight of the solid dosage form.
• a glidant is employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 0.65% by weight of the solid dosage form.
• Suitable lubricants include, without limitation, magnesium stearate, calcium stearate, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof.
• a lubricant may be employed in an amount ranging from about 0.1% to about 10%, preferably from about 2% to about 3% by weight of the solid dosage form (prior to any optional film coating).
• a lubricant is preferably employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 2% by weight of the solid dosage form.
• a lubricant is preferably employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 2% by weight of the solid dosage form.
• Suitable binders include, without limitation, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose (e.g., cellulose MK GR), and combinations thereof.
• a binder may be employed in an amount ranging from about 0.5% to about 40%, preferably in an amount of about 10% by weight of the solid dosage form (prior to any optional film coating).
• a binder is preferably employed in an amount ranging from about 0.5% to about 40%, more preferably in an amount of about 10% by weight of the solid dosage form.
• a binder is preferably employed in an amount ranging from about 0.5% to about 40%, more preferably in an amount of about 10% by weight of the solid dosage form.
• Suitable colorants include, without limitation, iron oxides such as yellow, red, and black iron oxide, and titanium dioxide and combinations thereof. When present, a colorant may be employed in an amount ranging from about 0.01% to about 0.1% by weight of the solid dosage form (prior to any optional film coating).
• monolayer tablets contain no colorant. Film coating for monolayer tablets are given in the example Tables
• the solid dosage forms of the first embodiment of the invention are monolayer or bilayer tablet dosage forms of suitable hardness, e.g., an average hardness ranging from about 60 N to about 350 N for monolayer forms and an average hardness ranging from about 100 N to about 350 N for bilayer forms. Such an average hardness is determined prior to the application of any film coating on the solid dosage forms.
• a preferred embodiment of this invention is directed to solid dosage forms which are film-coated.
• Suitable film coatings are known and commercially available or can be made according to known methods.
• the film coating material is a polymeric film coating material comprising materials such as hydroxypropylmethyl cellulose, polyethylene glycol, talc and colorant.
• the second embodiment of the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) blending valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• valsartan amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives, i.e., source, amount, etc.
• This embodiment can be in the form of all possible permutations, e.g., valsartan may be blended alone and amlodipine and hydrochlorothiazide may be added in the final blending step.
• valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives are blended to form a blended material. Blending can be accomplished using any suitable means such as a diffusion blender or diffusion mixer.
• the blended material is sieved to form a sieved material. Sieving can be accomplished using any suitable means.
• the sieved material is blended to form a blended/sieved material. Again blending can be accomplished using any suitable means.
• the blended/sieved material is compacted to form a compacted material.
• Compacting can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about 0.5 kN to about 90 kN, preferably about 20 kN to about 60 kN. Compaction may also be carried out by slugging the blended powders into large tablets that are then size-reduced.
• the compacted material is milled to form a milled material. Milling can be accomplished using any suitable means.
• the milled material is blended to form blended/milled material. Here again blending can be accomplished using any suitable means.
• the blended/milled material is compressed to form a monolayer solid dosage form. Compression can be accomplished using any suitable means. Typically compression is accomplished using a rotary tablet press. Compression force for such a rotary tablet press typically ranges from about 5 kN to about 40 kN.
• the method of the second embodiment comprises the step of (h) film coating the monolayer solid dosage form.
• film coating material i.e., components, amounts, etc.
• Film coating can be accomplished using any suitable means.
• this invention is directed to solid dosage forms of valsartan made according to the method of the second embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan amlodipine and HCTZ comprising the steps of a) blending valsartan and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine and hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the fourth embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, amlodipine, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the sixth embodiment.
• the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, hydrochlorothiazide, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.
• a preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form.
• this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the eighth embodiment.
• the tenth embodiment of the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation; (b) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form, wherein hydrochlorothiazide is present in the valsartan granulation and/or the amlodipine blend.
• the details regarding the valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives, i.e., source, amount, etc., are as set forth above with regard to the first embodiment of the invention.
• valsartan is granulated with pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation.
• Valsartan granulation can be accomplished by any suitable means.
• valsartan granulation is accomplished by (al) blending valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.
• Hydrochlorothiazide can be incorporated at step al and/or a6.
• step (al) can be accomplished using any suitable means.
• valsartan, pharmaceutically acceptable additives and optionally the hydrochlorothiazide are dispatched to a suitable vessel such as a diffusion blender or diffusion mixer.
• the sieving of step (a2) can be accomplished using any suitable means.
• the blending of step (a3) can be accomplished using any suitable means.
• the compacting of step (a4) can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about 0.5 kN to about 90 kN, preferably about 20-60 kN. Compaction may also be carried out by slugging the blended powders into large tablets that are then size-reduced.
• step (a5) can be accomplished using any suitable means.
• the compacted material is milled through a screening mill.
• the blending of step (a6) can be accomplished using any suitable means.
• the milled material is blended, often with a pharmaceutically acceptable additive such as a lubricant, in a diffusion blender.
• amlodipine is blended with pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine blend.
• Amlodipine granulation can be accomplished by any suitable means.
• blending step (b) comprises the process of granulating amlodipine.
• Amlodipine granulation can be accomplished by any suitable means including but not limited wet granulation, dry granulation, melt granulation or dry blend.
• amlodipine granulation is accomplished by (bl) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form an amlodipine granulation.
• Hydrochlorothiazide can be incorporated at step bl and/or b6. Hydrochlorothiazide can be incorporated by any suitable means including but not limited wet granulation, dry granulation, melt granulation or dry blend.
• step (bl) can be accomplished using any suitable means.
• step (b2) can be accomplished using any suitable means.
• step (b3) can be accomplished using any suitable means.
• the compacting of step (b2) can be accomplished using any suitable means.
• (b4) can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about
• step (b5) can be accomplished using any suitable means.
• the compacted material is milled through a screening mill.
• the blending of step (b6) can be accomplished using any suitable means.
• the valsartan granulation and the amlodipine blend are compressed together to form a bilayer solid dosage form.
• Compression can be accomplished using any suitable means. Typically compression is accomplished using a bilayer rotary tablet press. Typical compression force ranges from about 5 kN to about 40 kN.
• hydrochlorothiazide is present in one of the valsartan granulation and the amlodipine blend.
• the inclusion of hydrochlorothiazide in the bilayer solid dosage form is not optional; only its placement in the same, i.e., in the valsartan layer or in the amlodipine layer, is variable.
• hydrochlorothiazide may be present alone in a separate layer.
• the method of the tenth embodiment comprises the step of (d) film coating the bilayer solid dosage form.
• the details regarding the film coating material, i.e., components, amounts, etc., are as described above with regard to the first embodiment of the invention. Film coating can be accomplished using any suitable means.
• An eleventh embodiment of the present invention is directed to a bilayer solid dosage form of valsartan, amlodipine and HCTZ made according to the method of the tenth embodiment.
• this invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a valsartan granulation; (b) granulating hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a hydrochlorothiazide granulation; and (c) compressing the valsartan granulation and the hydrochlorothiazide granulation together to form a bilayer solid dosage form, wherein amlodipine is present in the valsartan granulation and/or the hydrochlorothiazide blend.
• step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.
• step (b) comprises a granulation process with the steps of (bl) blending hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form a hydrochlorothiazide granulation.
• Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form.
• Amlodipine can be incorporated at step al and/or a6, and at step bl and/or b6.
• Yet another embodiment of the invention is directed to a method of treating hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure.
• the method comprises administering a solid dosage form of valsartan, amlodipine and hydrochlorothiazide to a subject in need of such treatment.
• the solid dosage form is orally administered to the subject.
• a monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 1 below. Table 1.
• Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines subdivided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• a monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 2 below.
• Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub- divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• a monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 3 below. Table 3.
• Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines subdivided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• a monolayer solid dosage form of valsartan,amlodipine and HCTZ was made using the ingredients set forth in Table 4 below. Table 4.
• Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines subdivided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• a monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 5 below. Table 5.
• Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines subdivided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.
• a bilayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 6 below. Table 6.
• the valsartan is granulated by combining ingredients A-F in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient G in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-F.)
• the amlodipine besylate is granulated by combining ingredients H-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender.
• the valsartan is granulated by combining ingredients A-E in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient F in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-E.)
• the amlodipine besylate is granulated by combining ingredients G-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender.
• a bilayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 10 and 1 1 below.
• the valsartan is granulated by combining ingredients A-F in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient G in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-F.)
• the HCTZ is granulated by combining ingredients H-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender.

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Cardiology (AREA)
• Neurosurgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Diabetes (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Urology & Nephrology (AREA)
• Hematology (AREA)
• Hospice & Palliative Care (AREA)
• Obesity (AREA)
• Vascular Medicine (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Gastroenterology & Hepatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Priority Applications (14)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (2)

Family

ID=38662673

Family Applications (1)

Country Status (23)

Cited By (13)

Families Citing this family (15)

Citations (1)

Family Cites Families (13)

• 2007
  • 2007-06-25 PE PE2007000810A patent/PE20080991A1/es not_active Application Discontinuation
  • 2007-06-25 PE PE2011001722A patent/PE20120542A1/es not_active Application Discontinuation
  • 2007-06-25 AR ARP070102798A patent/AR061627A1/es not_active Application Discontinuation
  • 2007-06-26 JP JP2009518503A patent/JP2009542709A/ja active Pending
  • 2007-06-26 RU RU2009102273/15A patent/RU2449786C2/ru not_active IP Right Cessation
  • 2007-06-26 CL CL200701870A patent/CL2007001870A1/es unknown
  • 2007-06-26 KR KR1020087031581A patent/KR20090021191A/ko not_active Application Discontinuation
  • 2007-06-26 EP EP07799032A patent/EP2037893A2/en not_active Ceased
  • 2007-06-26 CN CN200780024142XA patent/CN101478956B/zh active Active
  • 2007-06-26 WO PCT/US2007/072097 patent/WO2008002905A2/en active Application Filing
  • 2007-06-26 CN CN2013100435988A patent/CN103169711A/zh active Pending
  • 2007-06-26 MX MX2008016532A patent/MX2008016532A/es not_active Application Discontinuation
  • 2007-06-26 BR BRPI0713785-0A patent/BRPI0713785A2/pt not_active IP Right Cessation
  • 2007-06-26 AU AU2007265138A patent/AU2007265138A1/en not_active Abandoned
  • 2007-06-26 NZ NZ573295A patent/NZ573295A/en not_active IP Right Cessation
  • 2007-06-26 CA CA002654986A patent/CA2654986A1/en not_active Abandoned
  • 2007-06-26 US US11/915,096 patent/US20100003321A1/en not_active Abandoned
  • 2007-06-26 TW TW096123057A patent/TW200808379A/zh unknown
• 2008
  • 2008-11-26 ZA ZA200810053A patent/ZA200810053B/xx unknown
  • 2008-12-08 IL IL195797A patent/IL195797A0/en unknown
  • 2008-12-18 EC EC2008008987A patent/ECSP088987A/es unknown
  • 2008-12-24 MA MA31506A patent/MA30529B1/fr unknown
  • 2008-12-26 TN TNP2008000538A patent/TNSN08538A1/en unknown
• 2009
  • 2009-01-20 NO NO20090314A patent/NO20090314L/no not_active Application Discontinuation
  • 2009-11-11 HK HK09110531.6A patent/HK1133818A1/xx not_active IP Right Cessation
• 2012
  • 2012-01-03 US US13/342,533 patent/US8475839B2/en active Active

Patent Citations (1)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events